Antiarrhythmic effects of cariporide, a novel Na+-H+ exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts.
Cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate: HOE642) is a novel Na+-H+ exchange subtype 1 inhibitor and has antiarrhythmic effects on ischemia/reperfusion arrhythmias without apparent cardiovascular effects in dogs and rats when given before coronary occlusion. The aim of this study was to determine the minimum effective dose and to examine the dose related effects of cariporide when it was administered before and during coronary occlusion as well as simultaneously with reperfusion. In the pre-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 140 to 36 (P < 0.01), 59 (P < 0.05) and 23 s (P < 0.01) with 0.03, 0.1 and 1 mg/kg, respectively, and reduced the incidence of reperfusion-induced ventricular tachycardia from 100 to 50 and 58% (P < 0.01), ventricular fibrillation from 83 to 8 and 0% (P < 0.01), and mortality from 75 to 8 and 8% (P < 0.01) with 0.1 and 1 mg/kg, respectively. In the post-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 92 to 37, 40, 42 (P < 0.05) and 24 s (P < 0.01) with 0.03, 0.1, 0.3 and 1 mg/kg, respectively, and the incidence of ventricular tachycardia from 100 to 53% (P < 0.01) by 1 mg/kg, and ventricular fibrillation from 87 to 33, 7 and 7% (P < 0.01), and the mortality from 73 to 27 (P < 0.05), 0 and 7% (P < 0.01) with 0.1, 0.3 and 1 mg/kg, respectively. In the group with simultaneous injection, both doses of cariporide (1 and 3 mg/kg) reduced the incidence of ventricular fibrillation from 83 to 42% (P < 0.05). The heart rate, blood pressure and QT interval did not change after drug treatment.
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Department of Pharmacology, Yamanashi Medical University, Japan.
Xue
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Hashimoto
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D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D016276:Ventricular Function / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide